Background fabry's disease is an x-linked recessive disorderthat results from a deficiency of -galactosidase. Left ventricularhypertrophy is one of the common manifestations in men withclassic hemizygous disease. Recently, several cases of an atypicalvariant of hemizygous Fabry's disease, with manifestations limitedto the heart, have been reported. Therefore, we assessed theincidence of hemizygosity for Fabry's disease among male patientswith left ventricular hypertrophy.
Methods We measured plasma -galactosidase activity in 230 consecutivemale patients with left ventricular hypertrophy. Clinical manifestationswere assessed, endomyocardial biopsies were performed, and thepatients were screened for mutations in the -galactosidase gene.
Results Seven of the 230 patients with left ventricular hypertrophy(3 percent) had low plasma -galactosidase activity (4 to 14percent of the mean value in normal controls). These seven unrelatedpatients, ranging in age from 55 to 72 years, did not have angiokeratoma,acroparesthesias, hypohidrosis, or corneal opacities, whichare typical manifestations of Fabry's disease. Endomyocardialbiopsy was performed in five patients and revealed marked sarcoplasmicvacuolization in all five. samples from four patients were examinedby electron microscopy and revealed typical lysosomal inclusionswith a concentric lamellar configuration in all four. Two patientshad novel missense mutations in exon 1 and exon 6. The remainingfive had no mutations in the coding region of the -galactosidasegene, but the amounts of the -galactosidase messenger RNA weremarkedly lower than normal.
Conclusions Seven unrelated patients with atypical variantsof hemizygous Fabry's disease were found among 230 men withleft ventricular hypertrophy. Fabry's disease should be consideredas a cause of unexplained left ventricular hypertrophy.
Fabry's disease is an X-linked recessive disease resulting froma deficiency of the lysosomal hydrolase -galactosidase.1,2,3This enzymatic defect leads to the progressive accumulationof glycosphingolipids, predominantly globotriaosylceramide,throughout the body, particularly in the skin, kidney, nervoussystem, eye, and heart.4 The clinical manifestations differbetween the classic form and the atypical hemizygous form. Inmale patients with the classic hemizygous form, acroparesthesias,hypohidrosis, corneal opacities, and dysfunction of the kidney,brain, and heart are observed.1 Various cardiac manifestations,including left ventricular hypertrophy, valvular involvement,and arrhythmias, have been reported.4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21
Recently, several cases of an atypical variant of Fabry's disease,with manifestations limited to the heart, have been reported.16,17,18,19In patients with this type of Fabry's disease, the diagnosiswas made by the pathological study of endomyocardial-biopsyspecimens or autopsy specimens of the heart. These patientshad left ventricular hypertrophy as a result of the depositionof globotriaosylceramide in the cardiomyocytes. However, therehas been only a single report of the incidence of Fabry's diseaseamong patients with cardiac symptoms; in that study the diseasewas found by endomyocardial biopsy.12 The purpose of the currentstudy was to clarify the incidence of Fabry's disease amongmale patients with left ventricular hypertrophy, to examinethe clinical characteristics of these patients, and to detectmutations in the -galactosidase gene.
Methods
We prospectively studied male patients who were seen at thecardiovascular division of Kagoshima University Hospital fromOctober 1992 to June 1993. All male patients who had cardiacsymptoms, cardiac murmurs, arrhythmias, hypertension, abnormalelectrocardiograms, or enlargement of the cardiac silhouetteon chest radiography were examined by echocardiography. A totalof 1603 male patients underwent echocardiography, and 230 (14percent) were found to have left ventricular hypertrophy. Thecriterion for the diagnosis of left ventricular hypertrophywas a ventricular-septum or posterior-wall thickness of at least13 mm (or both) on echocardiography.22 The patients with leftventricular hypertrophy ranged in age from 16 to 87 years (mean[±SD], 62±13). Eighty-nine normal, healthy malesubjects ranging from 14 to 80 years of age (mean, 52±19)were used as controls. The research protocol was reviewed andapproved by the review board of Kagoshima University Hospital.
Plasma -galactosidase activity was measured in all patientswith left ventricular hypertrophy and all normal subjects. Theassay was performed with the fluorogenic substrate 4-methylumbelliferyl--d-galactopyranoside(Sigma Chemical, St. Louis), with N-acetyl-d-galactosamine (NacalaiTesque, Kyoto, Japan) used as an inhibitor of -N-acetylgalactosaminidase.23Seven patients who had no or very low plasma -galactosidaseactivity were given a diagnosis of Fabry's disease.3 Lymphocyte-galactosidase activity was then measured in these patientsand in 43 controls. Clinical manifestations of Fabry's disease,such as angiokeratoma, acroparesthesias, hypohidrosis, cornealopacities, albuminuria, and cerebrovascular damage, were alsoassessed.
Endomyocardial biopsies were performed in the patients givena diagnosis of Fabry's disease after written informed consentwas obtained. The specimens were fixed in 10 percent formalinand embedded in paraffin. Sections were cut and stained withhematoxylin and eosin for light-microscopical analysis. Forelectron microscopy, the specimens were immersed in a fixativecontaining 3 percent glutaraldehyde and 2 percent paraformaldehydebuffered with 0.1 M phosphate buffer (pH 7.4). They were thenpost-fixed with osmium tetroxide, dehydrated in a graded seriesof ethanol baths, and embedded in epoxy resin. Ultrathin sectionswere cut, double-stained with uranyl acetate and lead citrate,and examined with an electron microscope (model H-7100, Hitachi,Tokyo, Japan).
Heparin-treated blood samples were obtained from the seven patientsgiven a diagnosis of Fabry's disease after they provided informedconsent. Genomic DNA was isolated from the whole blood witha DNA extractor WB kit (Wako Pure Chemical Industries, Osaka,Japan) according to the manufacturer's instructions. Lymphoblastcell lines were established for six of the seven patients (Patients2 through 7), with use of the Epstein–Barr virus.24 Thecell lines were maintained in RPMI-1640 medium supplementedwith 10 percent fetal-calf serum and 1 percent penicillin–streptomycin(GIBCO, Grand Island, N.Y.) at 37°C in 5 percent carbondioxide. A lymphoblast cell line for Patient 1 could not beestablished. Total RNA was prepared from the cultured lymphoblastsby the acid guanidium thiocyanate–phenol–chloroformextraction method.25 Poly(A)+RNA was purified by oligodeoxythymidine–cellulosecolumn chromatography.25
Northern hybridization analysis was performed with poly(A)+RNAas a sample according to the standard method.26 Poly(A)+RNAwas electrophoretically separated in formaldehyde–agarosegel, transferred by capillary blotting to a nylon membrane (Hybond-N,Amersham, Buckinghamshire, United Kingdom), and hybridized witha full-length -galactosidase complementary DNA (cDNA) probelabeled with [-32P]deoxycytidine triphosphate according to standardtechniques.26 After autoradiography, the filter was washed with0.1 percent sodium dodecyl sulfate in water at 95°C for10 minutes, and a second hybridization was performed with an[-32P]deoxycytidine triphosphate–labeled -actin cDNA asa control.
Four biotinylated sense oligonucleotide primers and four antisenseoligonucleotide primers were used to amplify exons 1 through7.27 The polymerase chain reaction (PCR) was used to amplifygenomic DNA from each of the seven patients with Fabry's diseasewith the respective primer sets. The double-stranded PCR productswere denatured, and the biotinylated single strands were isolatedby affinity capture with streptavidin-coated magnetic beads(Dynabeads M-280; Dynal, Norway). The biotinylated single-strandedPCR products were then subjected to dideoxy-chain-terminationsequencing with -galactosidase–specific sequencing primers.27
A study of the transient expression of -galactosidase was donewith COS-1 cells.28 We transfected COS-1 cells in 60-mm tissue-culturedishes with 20 µg of plasmid DNA per dish that containedeither normal or mutant -galactosidase cDNA, using the calciumphosphate–glycerol shock technique.29 The transfectedcells were incubated in Ham's F10 medium supplemented with 10percent fetal-calf serum, harvested in phosphate-buffered salineafter 72 hours, and used for the -galactosidase assay and immunoblotting.For immunoblotting, 25 µg of protein from cell lysateswas subjected to sodium dodecyl sulfate–polyacrylamide-gelelectrophoresis on a 12.5 percent slab gel, transferred to anylon membrane (Hybond-N), and allowed to react with an anti–-galactosidaseantibody.30
Results
Of the 230 patients who had left ventricular hypertrophy, 121had systemic hypertension, 27 had asymmetric septal hypertrophy,8 had apical hypertrophy, 9 had aortic valvular stenosis, and7 had aortic valvular regurgitation.31,32 Five of the 27 patientswith asymmetric septal hypertrophy and 5 of the 8 patients withapical hypertrophy also had systemic hypertension. The remaining58 patients did not have any findings indicating systemic hypertension,asymmetric septal hypertrophy, apical hypertrophy, aortic valvularstenosis, or aortic valvular regurgitation.
The values for plasma -galactosidase activity in the 89 controlsranged from 4.8 to 17.6 nmol per hour per milliliter (mean [±SD],8.4±2.4). Very low levels of plasma -galactosidase activitywere found in 7 of the 230 patients with left ventricular hypertrophy(3 percent). These values ranged from 0.4 to 1.2 nmol per hourper milliliter, approximately 4 to 14 percent of the mean valuein the controls. The values for -galactosidase activity in theremaining 223 patients ranged from 4.5 to 17.8 nmol per hourper milliliter (mean, 8.5±2.4) (Figure 1). The sevenpatients with low -galactosidase activity were diagnosed ashaving hemizygous Fabry's disease. The lymphocyte -galactosidaseactivity in Patients 2 through 7 ranged from 1.6 to 8.4 nmolper hour per milligram of protein (Table 1). These values wereapproximately 3 to 18 percent of the mean values in 43 controls(mean, 46.4±6.5; range, 33.4 to 60.9).
Figure 1. Plasma -Galactosidase Activity in 89 Normal Male Subjects and 230 Male Patients with Left Ventricular Hypertrophy (LVH).
The values in the normal subjects ranged from 4.8 to 17.6 nmol per hour per milliliter (mean, 8.4±2.4). In seven patients with left ventricular hypertrophy, the values ranged from 0.4 to 1.2 nmol per hour per milliliter. In the remaining 223 patients with left ventricular hypertrophy, the values ranged from 4.5 to 17.8 nmol per hour per milliliter (mean, 8.5±2.4).
Table 1. Characteristics of Seven Patients with Hemizygous Fabry's Disease.
Endomyocardial biopsies were performed in five of the sevenpatients with hemizygous Fabry's disease. The myocardial cellsshowed marked sarcoplasmic vacuolization, leaving large clearspaces in the paraffin-embedded sections stained with hematoxylinand eosin. Specimens from four of the patients were examinedby electron microscopy, and typical lysosomal inclusions witha concentric lamellar configuration were observed in the sarcoplasmof myocardial cells in all four (Figure 2A, Figure 2B, and Figure 2C).
Figure 2. Photomicrographs of Myocardial Cells in an Endomyocardial-Biopsy Specimen from Patient 4.
Panel A shows marked sarcoplasmic vacuolization, leaving large clear spaces in the myocardial cells (hematoxylin and eosin, x460). Panels B and C show typical lysosomal inclusions with a concentric lamellar configuration on electron microscopy. The black bar indicates 3 µm in Panel B, and 0.1 µm in Panel C.
Table 1 shows the clinical characteristics of the seven patientswith hemizygous Fabry's disease. The patients ranged in agefrom 55 to 72 years and were not related. Left ventricular wallthickness ranged from 13 to 20 mm. None of the patients hadasymmetric septal hypertrophy, apical hypertrophy, obstructionof the left ventricular outflow tract, or aortic valvular disease.Coronary angiograms showed normal coronary arteries in all sixpatients studied (Patients 1, 2, 3, 4, 6, and 7). two had historiesof a cerebrovascular accident without paresis. Computed tomographyrevealed cerebral hemorrhage (Patient 4) and infarction (Patient6) in two patients. One of these patients (Patient 4) had systemichypertension (blood pressure, 170/110 mm Hg), albuminuria, anda serum creatinine concentration of 1.3 mg per deciliter (115µmol per liter). Angiokeratoma, acroparesthesias, hypohidrosis,or corneal opacities were not observed in any of the seven patients.
Three of the seven patients had cardiac symptoms. Two had dyspnea(Patients 1 and 5), and one had palpitations (Patient 2). Thereason for echocardiographic examination was dyspnea in Patients1 and 5, palpitations in Patient 2, premature ventricular contractionsin Patients 3 and 6, systemic hypertension in Patient 4, andthe finding of left ventricular hypertrophy on electrocardiographyin Patient 7. Three patients (Patients 1, 3, and 6) had ventriculararrhythmias, and two (Patients 2 and 5) had supraventriculararrhythmias. None of the patients had a short PR interval ormitral-valve disease, including mitral-valve prolapse.
Genomic amplification and solid-phase direct sequencing analysisof single-stranded genomic DNA from the seven patients identifiedtwo missense mutations, in Patients 4 and 5 (Figure 3 and Table 2).The missense mutation in Patient 4 was a G-to-A transitionat nucleotide 888 in exon 6 of the coding sequence, which predictedthe substitution of isoleucine for methionine at residue 296(Met296Ile). The mutant cDNA expressed low -galactosidase activityin COS-1 cells in the subsequent expression study. The activityof the mutant cDNA was 24 percent that of the wild-type cDNA.The enzyme activity was proportional to the amount of enzymeprotein, as estimated by Western blotting (Figure 4). The mutantproduct expressed in Patient 4 therefore appears to maintaina normal level of catalytic activity per molecule. The missensemutation in Patient 5 was a G-to-C transition at nucleotide58 in exon 1 of the coding sequence, which predicted the substitutionof proline for alanine at residue 20 (Ala20Pro). This missensemutation is in the coding region for the signal peptide of -galactosidase.33
Figure 3. Partial DNA Sequence of -Galactosidase Exon 6 (Upper Panel), Indicating the G-to-A shift at Nucleotide 888 (Met296Ile) in Patient 4, and -Galactosidase Exon 1 (Lower Panel), Indicating the G-to-C shift at Nucleotide 58 (Ala20Pro)in Patient 5.
Figure 4.-Galactosidase Activity (Upper Panel) and Immunoblotting (Lower Panel) in COS-1 Cells Transiently Expressing -Galactosidase cDNA from Patient 4 (with the Met296Ile Mutation), a Normal Control Subject, and Cells Transfected with Expression Vector Only (Mock).
Northern analysis revealed moderate decreases in the amountsof -galactosidase messenger RNA in these two patients (Patients4 and 5), as compared with the control. In the other patients(Patients 2, 3, 6, and 7), no gene mutations were found in thefull coding region for -galactosidase, but the amounts of -galactosidasemessenger RNA were markedly decreased (Figure 5 and Table 2).
Figure 5. Northern Blot of -Galactosidase Messenger RNA and -Actin Messenger RNA in Patients 2 through 7 and a Normal Subject.
The amount of messenger RNA was moderately decreased in Patients 4 and 5 and markedly decreased in Patients 2, 3,6, and 7.
Discussion
We identified 7 patients with hemizygous Fabry's disease bymeasuring plasma -galactosidase in 230 unselected men with leftventricular hypertrophy. This biochemical examination has beenreported to be a reliable method of identifying hemizygotes.3,23Most cases of the atypical variant of hemizygous Fabry's diseasewith left ventricular hypertrophy have been identified by biopsyof the heart or at autopsy.16,17,18,19 We believe that the measurementof plasma -galactosidase activity may be clinically useful forscreening and identifying patients with Fabry's disease.
Fabry's disease is thought to be rare, and the estimated incidenceof classic hemizygous disease is approximately 1 in 40,000.1The frequency of the atypical variant has not been determined.In the present study, 230 of the 1603 male patients (14 percent)referred to the cardiology section of the Kagoshima UniversityHospital for the workup of cardiac symptoms, hypertension, orabnormal findings on electrocardiography or chest radiographyhad evidence of left ventricular hypertrophy on echocardiography.Seven of these patients (3 percent) were given a diagnosis ofhemizygous Fabry's disease. We could find only one other reporton the incidence of atypical Fabry's disease.12 In that report,endomyocardial biopsy revealed that 2 of the 22 patients withhypertrophic nonobstructive cardiomyopathy (9 percent) had Fabry'sdisease. On the basis of the current study and the earlier report,atypical Fabry's disease in patients with left ventricular hypertrophymay not be as rare as previously thought.
Recently, several patients with atypical variants of Fabry'sdisease, in which manifestations were limited to the heart,have been described.16,17,18,19 In our study, all seven of thehemizygotes had residual plasma -galactosidase activity, rangingfrom 4 to 14 percent of the value in normal male controls. Clinicalfindings in five of the seven patients were unremarkable exceptfor left ventricular hypertrophy. Six of the patients with Fabry'sdisease were found in a subgroup of 58 patients with otherwiseunexplained left ventricular hypertrophy.
Previously, four kinds of missense mutations in exon 5 (Asn215Ser)and exon 6 (Met296Val, Gln279Glu, and Arg301Gln) have been reportedin atypical variants of Fabry's disease with manifestationsconfined to the heart.19,27,28,34 We found two novel mutations,Met296Ile (in Patient 4) and Ala20Pro (in Patient 5), that differfrom the two mutations — Gln279Glu and Arg301Gln —that have previously been found in Japanese patients.
In Patient 4, a G-to-A transition at nucleotide 888 was identifiedthat predicted the substitution of isoleucine for methionineat residue 296. Von Scheidt et al.19 reported a missense mutationat the same codon in a variant form of Fabry's disease: an A-to-Gtransition at nucleotide 886, causing the substitution of valinefor methionine (Met296Val). They predicted that the Met296Valmutation would replace a region of random coil with a -pleated–sheetmotif in the secondary structure of the enzyme. Both isoleucineand valine, which take the place of methionine in the mutantforms, are hydrophobic amino acids, and the mutant proteinsexpressed as a result of the Met296Ile and Met296Val mutationsare probably structurally similar to each other. The resultsof the Northern blotting and expression analyses of Met296Ilerevealed that the amount of the -galactosidase messenger RNAwas moderately decreased and the product expressed by the residualmessenger RNA seemed to retain the normal level of catalyticactivity per molecule but might be degraded more quickly thannormal.
In Patient 5, a G-to-C transition at nucleotide 58 was identified.This mutation resulted in the substitution of proline for alaninein the coding region for the signal peptide. Because the signalpeptide is known to be important in the intracellular transportof lysosomal matrix enzymes, including -galactosidase, a structuralchange in the signal peptide may interfere with the expressionof -galactosidase activity.
We could not find any mutations in the coding regions of eitherthe signal peptide or the enzyme subunit in the other five patients.However, the results of the Northern blot analysis revealedthat the amounts of the -galactosidase messenger RNA were markedlydecreased in the four other patients in whom it was measured.In these patients, there are presumably some mutations outsidethe coding region that involve the transcription of -galactosidase.Further genetic analysis should clarify the pathogenesis ofFabry's disease in these patients.
In conclusion, we detected Fabry's disease in 3 percent of unselectedmale patients with left ventricular hypertrophy who were referredto a cardiology clinic in Japan. Fabry's disease was found in10 percent of the patients who had no other underlying causeof left ventricular hypertrophy. This atypical variant of Fabry'sdisease, with clinical manifestations limited to the heart,may be more common than previously believed. Fabry's diseaseshould be considered in the differential diagnosis of male patientswith unexplained left ventricular hypertrophy.
Supported in part by a Research Grant for Chronic IntractableDisease from the Ministry of Health and Welfare of Japan andby grants from the Ministry of Education, Science and Cultureof Japan; the Kagoshima Prefectural Government; the Ono MedicalResearch Foundation; and the Naito Foundation.
We are indebted to Drs. Christine M. Eng and Robert J. Desnick,Department of Human Genetics, Mount Sinai School of Medicine,New York, for teaching us how to perform the sequence analysis;to Dr. Tamotsu Kanzaki, Department of Dermatology, KagoshimaUniversity Hospital, for his helpful discussion of these cases;to Dr. Mitsuhiro Osame, Third Department of Internal Medicine,Kagoshima University Hospital, for his assistance in measuringthe enzyme activity; and to Dr. Patricia C. Come, Departmentof Cardiology, Brigham and Women's Hospital, Boston, for reviewingthe manuscript.
Source Information
From the First Department of Internal Medicine (S.N., T.T., M.M., C.K., A.T., M.T., H.T.), the First Department of Pathology (A.Y.), and the Third Department of Internal Medicine (M.K.), Faculty of Medicine, Kagoshima University, Kagoshima, Japan; and the Department of Clinical Genetics, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan (H.H., H.S.).
Address reprint requests to Dr. Hiromitsu Tanaka at the First Department of Internal Medicine, Faculty of Medicine, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890, Japan.
References
Desnick RJ, Ioannou YA, Eng CM. -Galactosidase A deficiency: Fabry disease. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The metabolic and molecular bases of inherited disease. 7th ed. Vol. 2. New York: McGraw-Hill, 1995:2741-84.
Brady RO, Gal AE, Bradley RM, Martensson E, Warshaw AL, Laster L. Enzymatic defect in Fabry's disease: ceramidetrihexosidase deficiency. N Engl J Med 1967;276:1163-1167.
Desnick RJ, Allen KY, Desnick SJ, Raman MK, Bernlohr RW, Krivit W. Fabry's disease: enzymatic diagnosis of hemizygotes and heterozygotes: -galactosidase activities in plasma, serum, urine, and leukocytes. J Lab Clin Med 1973;81:157-171. [Medline]
Ferrans VJ, Hibbs RG, Burda CD. The heart in Fabry's disease: a histochemical and electron microscopic study. Am J Cardiol 1969;24:95-110.
Roudebush CP, Foerster JM, Bing OHL. The abbreviated PR interval of Fabry's disease. N Engl J Med 1973;289:357-358.
Becker AE, Schoorl R, Balk AG, van der Heide RM. Cardiac manifestations of Fabry's disease: report of a case with mitral insufficiency and electrocardiographic evidence of myocardial infarction. Am J Cardiol 1975;36:829-835. [CrossRef][Medline]
Desnick RJ, Blieden LC, Sharp HL, Hofschire PJ, Moller JH. Cardiac valvular anomalies in Fabry disease: clinical, morphologic, and biochemical studies. Circulation 1976;54:818-825. [Free Full Text]
Mehta J, Tuna N, Moller JH, Desnick RJ. Electrocardiographic and vectorcardiographic abnormalities in Fabry's disease. Am Heart J 1977;93:699-705. [Medline]
Matsui S, Murakami E, Takekoshi N, Hiramaru Y, Kin T. Cardiac manifestations of Fabry's disease: report of a case with pulmonary regurgitation diagnosed on the basis of endomyocardial biopsy findings. Jpn Circ J 1977;41:1023-1036. [Medline]
Bass JL, Shrivastava S, Grabowski GA, Desnick RJ, Moller JH. The M-mode echocardiogram in Fabry's disease. Am Heart J 1980;100:807-812. [CrossRef][Medline]
Colucci WS, Lorell BH, Schoen FJ, Warhol MJ, Grossman W. Hypertrophic obstructive cardiomyopathy due to Fabry's disease. N Engl J Med 1982;307:926-928. [Medline]
Kuhn H, Köhler E, Hort W, Frenzel H. Concealed myocardial storage disease (Fabry's disease): pitfalls in the diagnosis of hypertrophic nonobstructive cardiomyopathy. Circulation 1982;66:Suppl II:II-117.abstract
Sakuraba H, Yanagawa Y, Igarashi T, et al. Cardiovascular manifestations in Fabry's disease: a high incidence of mitral valve prolapse in hemizygotes and heterozygotes. Clin Genet 1986;29:276-283. [Medline]
Goldman ME, Cantor R, Schwartz MF, Baker M, Desnick RJ. Echocardiographic abnormalities and disease severity in Fabry's disease. J Am Coll Cardiol 1986;7:1157-1161. [Abstract]
Yanagawa Y, Sakuraba H. Cardiovascular manifestations in Fabry's disease -- age-related changes in hemizygotes and heterozygotes. Acta Paediatr Jpn 1988;30:38-48. [Medline]
Elleder M, Bradova V, Smid F, et al. Cardiocyte storage and hypertrophy as a sole manifestation of Fabry's disease: report on a case simulating hypertrophic non-obstructive cardiomyopathy. Virchows Arch A Pathol Anat Histopathol 1990;417:449-455. [CrossRef][Medline]
Ogawa K, Sugamata K, Funamoto N, et al. Restricted accumulation of globotriaosylceramide in the hearts of atypical cases of Fabry's disease. Hum Pathol 1990;21:1067-1073. [CrossRef][Medline]
Nagao Y, Nakashima H, Fukuhara Y, et al. Hypertrophic cardiomyopathy in late-onset variant of Fabry disease with high residual activity of -galactosidase A. Clin Genet 1991;39:233-237. [Medline]
von Scheidt W, Eng CM, Fitzmaurice TF, et al. An atypical variant of Fabry's disease with manifestations confined to the myocardium. N Engl J Med 1991;324:395-399. [Medline]
Fisher EA, Desnick RJ, Gordon RE, Eng CM, Griepp R, Goldman ME. Fabry disease: an unusual cause of severe coronary disease in a young man. Ann Intern Med 1992;117:221-223.
Ikari Y, Kuwako K, Yamaguchi T. Fabry's disease with complete atrioventricular block: histological evidence of involvement of the conduction system. Br Heart J 1992;68:323-325. [Free Full Text]
Felner JM. Echocardiography. In: Hurst JW, Schlant RC, Rackley CE, Sonnenblick EH, Wenger NK, eds. The heart, arteries and veins. 7th ed. New York: McGraw-Hill, 1990:1990-2035.
Mayes JS, Scheerer JB, Sifers RN, Donaldson ML. Differential assay for lysosomal alpha-galactosidase in human tissues and its application to Fabry's disease. Clin Chim Acta 1981;112:247-251. [CrossRef][Medline]
Anderson MA, Gusella JF. Use of cyclosporin A in establishing Epstein-Barr virus-transformed human lymphoblastoid cell lines. In Vitro 1984;20:856-858. [Medline]
Davis LG, Dibner MD, Battey JF. Basic methods in molecular biology. New York: Elsevier, 1986:130-42.
Sambrook J, Fritsch EF, Maniatis T. Molecular cloning: a laboratory manual. 2nd ed. Cold Spring Harbor, N.Y.: Cold Spring Harbor Laboratory, 1989.
Eng CM, Resnick-Silverman LA, Niehaus DJ, Astrin KH, Desnick RJ. Nature and frequency of mutations in the -galactosidase A gene that cause Fabry disease. Am J Hum Genet 1993;53:1186-1197. [Medline]
Ishii S, Sakuraba H, Suzuki Y. Point mutations in the upstream region of the -galactosidase A gene exon 6 in an atypical variant of Fabry disease. Hum Genet 1992;89:29-32. [Medline]
Koide T, Ishiura M, Iwai K, et al. A case of Fabry's disease in a patient with no -galactosidase A activity caused by a single amino acid substitution of Pro-40 by Ser. FEBS Lett 1990;259:353-356. [CrossRef][Medline]
Ishii S, Kase R, Sakuraba H, et al. Human -galactosidase gene expression: significance of two peptide regions encoded by exons 1-2 and 6. Biochim Biophys Acta 1994;1204:265-270. [CrossRef][Medline]
Henry WL, Clark CE, Epstein SE. Asymmetric septal hypertrophy: echocardiographic identification of the pathognomonic anatomic abnormality of IHSS. Circulation 1973;47:225-233. [Free Full Text]
Webb JG, Sasson Z, Rakowski H, Liu P, Wigle ED. Apical hypertrophic cardiomyopathy: clinical follow-up and diagnostic correlates. J Am Coll Cardiol 1990;15:83-90. [Abstract]
Bishop DF, Kornreich R, Desnick RJ. Structural organization of the human -galactosidase A gene: further evidence for the absence of a 3' untranslated region. Proc Natl Acad Sci U S A 1988;85:3903-3907. [Free Full Text]
Sakuraba H, Oshima A, Fukuhara Y, et al. Identification of point mutations in the -galactosidase A gene in classical and atypical hemizygotes with Fabry disease. Am J Hum Genet 1990;47:784-789. [Medline]
Lin, H.-Y., Chong, K.-W., Hsu, J.-H., Yu, H.-C., Shih, C.-C., Huang, C.-H., Lin, S.-J., Chen, C.-H., Chiang, C.-C., Ho, H.-J., Lee, P.-C., Kao, C.-H., Cheng, K.-H., Hsueh, C., Niu, D.-M.
(2009). High Incidence of the Cardiac Variant of Fabry Disease Revealed by Newborn Screening in the Taiwan Chinese Population. Circ Cardiovasc Genet
2: 450-456
[Abstract][Full Text]
Oqvist, B., Brenner, B. M., Oliveira, J. P., Ortiz, A., Schaefer, R., Svarstad, E., Wanner, C., Zhang, K., Warnock, D. G.
(2009). Nephropathy in Fabry disease: the importance of early diagnosis and testing in high-risk populations. Nephrol Dial Transplant
24: 1736-1743
[Full Text]
De Cobelli, F., Esposito, A., Belloni, E., Pieroni, M., Perseghin, G., Chimenti, C., Frustaci, A., Del Maschio, A.
(2009). Delayed-Enhanced Cardiac MRI for Differentiation of Fabry's Disease from Symmetric Hypertrophic Cardiomyopathy. Am. J. Roentgenol.
192: W97-W102
[Abstract][Full Text]
Schoenmakere, G. D., Poppe, B., Wuyts, B., Claes, K., Cassiman, D., Maes, B., Verbeelen, D., Vanholder, R., Kuypers, D. R., Lameire, N., De Paepe, A., Terryn, W.
(2008). Two-tier approach for the detection of alpha-galactosidase A deficiency in kidney transplant recipients. Nephrol Dial Transplant
23: 4044-4048
[Abstract][Full Text]
Chimenti, C., Morgante, E., Tanzilli, G., Mangieri, E., Critelli, G., Gaudio, C., Russo, M. A., Frustaci, A.
(2008). Angina in Fabry Disease Reflects Coronary Small Vessel Disease. Circ Heart Fail
1: 161-169
[Abstract][Full Text]
Joshi, S. B., Ahmar, W., Lee, G., Aggarwal, A.
(2008). Fabry's disease presenting as ventricular tachycardia and Left Ventricular 'Hypertrophy'. Eur J Echocardiogr
9: 697-699
[Abstract][Full Text]
Kounas, S., Demetrescu, C., Pantazis, A. A., Keren, A., Lee, P. J., Hughes, D., Mehta, A., Elliott, P. M.
(2008). The Binary Endocardial Appearance Is a Poor Discriminator of Anderson-Fabry Disease From Familial Hypertrophic Cardiomyopathy. J Am Coll Cardiol
51: 2058-2061
[Abstract][Full Text]
Hughes, D A, Elliott, P M, Shah, J, Zuckerman, J, Coghlan, G, Brookes, J, Mehta, A B
(2008). Effects of enzyme replacement therapy on the cardiomyopathy of Anderson Fabry disease: a randomised, double-blind, placebo-controlled clinical trial of agalsidase alfa. Heart
94: 153-158
[Abstract][Full Text]
Terryn, W., Poppe, B., Wuyts, B., Claes, K., Maes, B., Verbeelen, D., Vanholder, R., De Boeck, K., Lameire, N., De Paepe, A., De Schoenmakere, G.
(2008). Two-tier approach for the detection of alpha-galactosidase A deficiency in a predominantly female haemodialysis population. Nephrol Dial Transplant
23: 294-300
[Abstract][Full Text]
Andrade, J., Waters, P. J., Singh, R. S., Levin, A., Toh, B.-C., Vallance, H. D., Sirrs, S.
(2008). Screening for Fabry Disease in Patients with Chronic Kidney Disease: Limitations of Plasma {alpha}-Galactosidase Assay as a Screening Test. CJASN
3: 139-145
[Abstract][Full Text]
Monserrat, L., Gimeno-Blanes, J. R., Marin, F., Hermida-Prieto, M., Garcia-Honrubia, A., Perez, I., Fernandez, X., de Nicolas, R., de la Morena, G., Paya, E., Yague, J., Egido, J.
(2007). Prevalence of Fabry Disease in a Cohort of 508 Unrelated Patients With Hypertrophic Cardiomyopathy. J Am Coll Cardiol
50: 2399-2403
[Abstract][Full Text]
Ackerman, M. J., Landstrom, A. P.
(2007). Detection of Subclinical Fabry Disease in Patients Presenting With Hypertrophic Cardiomyopathy. J Am Coll Cardiol
50: 2404-2405
[Full Text]
Warnock, D. G.
(2007). Enzyme Replacement Therapy and Fabry Kidney Disease: Quo Vadis?. J. Am. Soc. Nephrol.
18: 1368-1370
[Full Text]
Linhart, A., Elliott, P. M
(2007). The heart in Anderson-Fabry disease and other lysosomal storage disorders. Heart
93: 528-535
[Full Text]
Banikazemi, M., Bultas, J., Waldek, S., Wilcox, W. R., Whitley, C. B., McDonald, M., Finkel, R., Packman, S., Bichet, D. G., Warnock, D. G., Desnick, R. J., for the Fabry Disease Clinical Trial Study Group*,
(2007). Agalsidase-Beta Therapy for Advanced Fabry Disease: A Randomized Trial. ANN INTERN MED
146: 77-86
[Abstract][Full Text]
Developed in Collaboration With the European Heart, , Zipes, D. P., Camm, A. J., Borggrefe, M., Buxton, A. E., Chaitman, B., Fromer, M., Gregoratos, G., Klein, G., Moss, A. J., Myerburg, R. J., Priori, S. G., Quinones, M. A., Roden, D. M., Silka, M. J., Tracy, C., Smith, S. C. Jr, Jacobs, A. K., Adams, C. D., Antman, E. M., Anderson, J. L., Hunt, S. A., Halperin, J. L., Nishimura, R., Ornato, J. P., Page, R. L., Riegel, B., Priori, S. G., Blanc, J.-J., Budaj, A., Camm, A. J., Dean, V., Deckers, J. W., Despres, C., Dickstein, K., Lekakis, J., McGregor, K., Metra, M., Morais, J., Osterspey, A., Tamargo, J. L., Zamorano, J. L.
(2006). ACC/AHA/ESC 2006 Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death: A Report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Develop Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death). J Am Coll Cardiol
48: e247-e346
[Full Text]
Writing Committee Members, , Zipes, D. P., Camm, A. J., Borggrefe, M., Buxton, A. E., Chaitman, B., Fromer, M., Gregoratos, G., Klein, G., Moss, A. J., Myerburg, R. J., Priori, S. G., Quinones, M. A., Roden, D. M., Silka, M. J., Tracy, C., ESC Committee for Practice Guidelines, , Priori, S. G., Blanc, J.-J., Budaj, A., Camm, A. J., Dean, V., Deckers, J. W., Despres, C., Dickstein, K., Lekakis, J., McGregor, K., Metra, M., Morais, J., Osterspey, A., Tamargo, J. L., Zamorano, J. L., ACC/AHA Task Force Members, , Smith, S. C. Jr, Jacobs, A. K., Adams, C. D., Antman, E. M., Anderson, J. L., Hunt, S. A., Halperin, J. L., Nishimura, R., Ornato, J. P., Page, R. L., Riegel, B.
(2006). ACC/AHA/ESC 2006 guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: A report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Develop Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death) Developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. Europace
8: 746-837
[Full Text]
Morita, H., Larson, M. G., Barr, S. C., Vasan, R. S., O'Donnell, C. J., Hirschhorn, J. N., Levy, D., Corey, D., Seidman, C. E., Seidman, J.G., Benjamin, E. J.
(2006). Single-Gene Mutations and Increased Left Ventricular Wall Thickness in the Community: The Framingham Heart Study. Circulation
113: 2697-2705
[Abstract][Full Text]
Pieroni, M., Chimenti, C., De Cobelli, F., Morgante, E., Del Maschio, A., Gaudio, C., Russo, M. A., Frustaci, A.
(2006). Fabry's Disease Cardiomyopathy: Echocardiographic Detection of Endomyocardial Glycosphingolipid Compartmentalization. J Am Coll Cardiol
47: 1663-1671
[Abstract][Full Text]
Morimoto, S.-i., Sugiura, A., Iwase, M., Kubo, N., Hiramitsu, S., Uemura, A., Ohtsuki, M., Kato, S., Kato, Y., Hishida, H.
(2006). Relief of Left Ventricular Outflow Obstruction by Cibenzoline in a Patient With Fabry's Disease: A Case Report. ANGIOLOGY
57: 241-245
[Abstract]
Nance, C. S., Klein, C. J., Banikazemi, M., Dikman, S. H., Phelps, R. G., McArthur, J. C., Rodriguez, M., Desnick, R. J.
(2006). Later-Onset Fabry Disease: An Adult Variant Presenting With the Cramp-Fasciculation Syndrome.. Arch Neurol
63: 453-457
[Abstract][Full Text]
Yang, Z., McMahon, C. J., Smith, L. R., Bersola, J., Adesina, A. M., Breinholt, J. P., Kearney, D. L., Dreyer, W. J., Denfield, S. W., Price, J. F., Grenier, M., Kertesz, N. J., Clunie, S. K., Fernbach, S. D., Southern, J. F., Berger, S., Towbin, J. A., Bowles, K. R., Bowles, N. E.
(2005). Danon Disease as an Underrecognized Cause of Hypertrophic Cardiomyopathy in Children. Circulation
112: 1612-1617
[Abstract][Full Text]
De Backer, J., Matthys, D., Gillebert, T.C., De Paepe, A., De Sutter, J.
(2005). The use of Tissue Doppler Imaging for the assessment of changes in myocardial structure and function in inherited cardiomyopathies. Eur J Echocardiogr
6: 243-250
[Abstract][Full Text]
Weidemann, F., Breunig, F., Beer, M., Sandstede, J., Stork, S., Voelker, W., Ertl, G., Knoll, A., Wanner, C., Strotmann, J. M.
(2005). The variation of morphological and functional cardiac manifestation in Fabry disease: potential implications for the time course of the disease. Eur Heart J
26: 1221-1227
[Abstract][Full Text]
Arad, M., Maron, B. J., Gorham, J. M., Johnson, W. H. Jr., Saul, J. P., Perez-Atayde, A. R., Spirito, P., Wright, G. B., Kanter, R. J., Seidman, C. E., Seidman, J.G.
(2005). Glycogen Storage Diseases Presenting as Hypertrophic Cardiomyopathy. NEJM
352: 362-372
[Abstract][Full Text]
Larralde, M., Boggio, P., Amartino, H., Chamoles, N.
(2004). Fabry Disease: A Study of 6 Hemizygous Men and 5 Heterozygous Women With Emphasis on Dermatologic Manifestations. Arch Dermatol
140: 1440-1446
[Abstract][Full Text]
Chimenti, C., Pieroni, M., Morgante, E., Antuzzi, D., Russo, A., Russo, M. A., Maseri, A., Frustaci, A.
(2004). Prevalence of Fabry Disease in Female Patients With Late-Onset Hypertrophic Cardiomyopathy. Circulation
110: 1047-1053
[Abstract][Full Text]
Charron, P, Villard, E, Sebillon, P, Laforet, P, Maisonobe, T, Duboscq-Bidot, L, Romero, N, Drouin-Garraud, V, Frebourg, T, Richard, P, Eymard, B, Komajda, M
(2004). Danon's disease as a cause of hypertrophic cardiomyopathy: a systematic survey. Heart
90: 842-846
[Abstract][Full Text]
Nagueh, S F
(2003). Fabry disease. Heart
89: 819-820
[Full Text]
Ommen, S R, Nishimura, R A, Edwards, W D
(2003). Fabry disease: a mimic for obstructive hypertrophic cardiomyopathy?. Heart
89: 929-930
[Full Text]
Pieroni, M., Chimenti, C., Ricci, R., Sale, P., Russo, M. A., Frustaci, A.
(2003). Early Detection of Fabry Cardiomyopathy by Tissue Doppler Imaging. Circulation
107: 1978-1984
[Abstract][Full Text]
Desnick, R. J., Brady, R., Barranger, J., Collins, A. J., Germain, D. P., Goldman, M., Grabowski, G., Packman, S., Wilcox, W. R.
(2003). Fabry Disease, an Under-Recognized Multisystemic Disorder: Expert Recommendations for Diagnosis, Management, and Enzyme Replacement Therapy. ANN INTERN MED
138: 338-346
[Abstract][Full Text]
Breunig, F., Wanner, C.
(2003). Enzyme replacement therapy for Fabry disease: proving the clinical benefit. Nephrol Dial Transplant
18: 7-9
[Full Text]
Tse, K.-C., Chan, K.-W., Tin, V. P.-C., Yip, P.-S., Tang, S., Li, F.-K., Ho, Y.-W., Lai, K.-N., Chan, T.-M.
(2003). Clinical features and genetic analysis of a Chinese kindred with Fabry's disease. Nephrol Dial Transplant
18: 182-186
[Abstract][Full Text]
Doi, Y, Toda, G, Yano, K
(2003). Sisters with atypical Fabry's disease with complete atrioventricular block. Heart
89: e2-2
[Abstract][Full Text]
Takahashi, H., Hirai, Y., Migita, M., Seino, Y., Fukuda, Y., Sakuraba, H., Kase, R., Kobayashi, T., Hashimoto, Y., Shimada, T.
(2002). Long-term systemic therapy of Fabry disease in a knockout mouse by adeno-associated virus-mediated muscle-directed gene transfer. Proc. Natl. Acad. Sci. USA
99: 13777-13782
[Abstract][Full Text]
Veinot, J. P., Elliott, P.M., Sachdev, B., McKenna, W.J., Takenaka, T., Teraguchi, H., Tei, C., Lee, P.
(2002). Prevalence of Anderson-Fabry Disease in Male Patients With Late Onset Hypertrophic Cardiomyopathy * Response. Circulation
106
: e73-e73
[Full Text]
MEHTA, A.
(2002). New developments in the management of Anderson-Fabry disease. QJM
95: 647-653
[Abstract][Full Text]
Grunfeld, J.-P., Chauveau, D., Levy, M.
(2002). Anderson-Fabry Disease: Its Place among Other Genetic Causes of Renal Disease. J. Am. Soc. Nephrol.
13: S126-129
[Full Text]
Pastores, G. M., Lien, Y.-H. H.
(2002). Biochemical and Molecular Genetic Basis of Fabry Disease. J. Am. Soc. Nephrol.
13: S130-133
[Full Text]
Kampmann, C., Baehner, F., Ries, M., Beck, M.
(2002). Cardiac Involvement in Anderson-Fabry Disease. J. Am. Soc. Nephrol.
13: S147-149
[Full Text]
Frustaci, A., Pieroni, M., Chimenti, C.
(2002). Late-onset primary LVH HCM versus cardiac fabry variant. J Am Coll Cardiol
39: 1405-1406
[Full Text]
Sachdev, B., Takenaka, T., Teraguchi, H., Tei, C., Lee, P., McKenna, W.J., Elliott, P.M.
(2002). Prevalence of Anderson-Fabry Disease in Male Patients With Late Onset Hypertrophic Cardiomyopathy. Circulation
105: 1407-1411
[Abstract][Full Text]
Frustaci, A., Chimenti, C., Ricci, R., Natale, L., Russo, M. A., Pieroni, M., Eng, C. M., Desnick, R. J.
(2001). Improvement in Cardiac Function in the Cardiac Variant of Fabry's Disease with Galactose-Infusion Therapy. NEJM
345: 25-32
[Full Text]
Brady, R. O., Schiffmann, R.
(2000). Clinical Features of and Recent Advances in Therapy for Fabry Disease. JAMA
284: 2771-2775
[Abstract][Full Text]
Lidove, O., Joly, D., Rossignol, P., Robino, C., N'Guessau, K., Grunfeld, J. P.
(2000). A man with proteinuria, familial history of kidney disease, painful extremities and cutaneous lesions. Nephrol Dial Transplant
15: 433-435
[Full Text]
Bogardus, S. T. Jr, Concato, J., Feinstein, A. R.
(1999). Clinical Epidemiological Quality in Molecular Genetic Research: The Need for Methodological Standards. JAMA
281: 1919-1926
[Abstract][Full Text]
(1995). Fabry's Disease May Be a Cause of LVH in Some. Journal Watch Cardiology
1995: 14-14
[Full Text]
Takenaka, T., Murray, G. J., Qin, G., Quirk, J. M., Ohshima, T., Qasba, P., Clark, K., Kulkarni, A. B., Brady, R. O., Medin, J. A.
(2000). Long-term enzyme correction and lipid reduction in multiple organs of primary and secondary transplanted Fabry mice receiving transduced bone marrow cells. Proc. Natl. Acad. Sci. USA
97: 7515-7520
[Abstract][Full Text]
-galactosidase. Left ventricular hypertrophy is one of the common manifestations in men with classic hemizygous disease. Recently, several cases of an atypical variant of hemizygous Fabry's disease, with manifestations limited to the heart, have been reported. Therefore, we assessed the incidence of hemizygosity for Fabry's disease among male patients with left ventricular hypertrophy. 
-actin cDNA as a control. 
Previous
